tbuckley/cabot-search huggingface dataset:
Abstract 520: Investigation the function and application of spermine in castration-resistant prostate cancer
Authors: Jingkai Sun, Peter Ka-Fung Chiu, Tingting Xie, Jeremy Yuen-Chun Teoh, Chi-Fai Ng
Journal: Cancer Research (2023)

Abstract Introduction &amp; Objectives: Spermine (Spm) is a typical metabolite that is highly concentrated in healthy prostate epithelium maintaining cell growth and functions. Our previous studies found that Spm was significantly decreased in PCa tissue than in benign prostate tissue, as was the urinary Spm in PCa. This study aimed to reveal the specific role of Spm in PCa. Materials &amp; Methods: In this study, Spm was resupplied to castration-resistant prostate cancer (CRPC) cells (PC3 and DU145). Following Spm treatment, MTT (methyl thiazolyl tetrazolium) and EdU (5-ethynyl-2’-deoxyuridine) assay were used to determine the cell proliferation of CRPC cell lines. Cellular apoptosis, cell cycle distribution and mitochondrial membrane potential were analyzed by flow cytometry. Cellular reactive Oxygen species (ROS) level was measured by fluorescence microscope. mRNA and ATAC sequencing in spermine-treated CRPC cells were performed to reveal the related mechanism for Spm effect. Results: In the in vitro studies, Spm was found to inhibit the cell viability of CRPC cells. Transwell assays demonstrated that Spm impaired migration and invasion ability. And Spm blocked tumor progression by inducing G2/M arrest and cellular apoptosis in CRPC cells dose-dependently. mRNA seq revealed that a series of genes were altered after Spm treatment and indicated the potential functional pathway of Spm might be mitophagy. We integrated mRNA seq data with ATAC seq profiles and accessed those genes regulated by polyamine metabolism and Spm-induced mitophagy. Results showed the sequencing tracks for the HMOX1 locus contain higher ATAC-seq peaks at the promoter under Spm treatment. Spm could affect oxidative phosphorylation which will lead to mitophagy and mitochondrial metabolism by modulating the transcriptional accessibility of genes. After Spm treatment, cellular ROS was upregulated while the mitochondrial membrane potential collapsed. Subsequently, western blot results showed that PINK1-mediated mitophagy related-proteins were significantly regulated. Conclusion: Our results indicated that Spm treatment led to mitochondrial dysfunction and subsequently degraded through mitophagy in CRPC cells. Our findings could provide a theoretical basis and have preliminary clinical implications in developing Spm as a promising agent against CRPC by inducing cellular mitophagy in CRPC cells. Citation Format: Jingkai Sun, Peter Ka-Fung Chiu, Tingting Xie, Jeremy Yuen-Chun Teoh, Chi-Fai Ng. Investigation the function and application of spermine in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 520.
Abstract 5710: Detection and monitoring of t(11;14) in liquid biopsies from patients with relapsed/refractory multiple myeloma treated with venetoclax-based regimens
Authors: Xiaotong Li, Lao H. Saal, Christian Brueffer, Yilun Chen, Johanna Asklin, Saman Alvi, Srinivas Venkatram, Jeremy A. Ross
Journal: Cancer Research (2023)

Abstract Venetoclax (Ven) is a selective B-cell lymphoma 2 inhibitor being studied in t(11;14)+ relapsed/refractory multiple myeloma (MM) Detection of t(11;14) in MM requires bone marrow (BM) aspiration and evaluation of CD138+ plasma cells by fluorescence in situ hybridization (FISH) Innovative techniques may provide less invasive detection of t(11;14) in liquid biopsies Here we present results of the SAGAsign® integrated approach combining low-coverage whole-genome sequencing (WGS) to characterize t(11;14) breakpoints together with personalized digital polymerase chain reaction (dPCR) assays to efficiently detect and monitor the genomic rearrangements in circulating tumor DNA (ctDNA) Baseline BM aspirates were collected from 270 patients (pts) from Ven clinical trials (NCT02755597, NCT01794520, NCT03314181, NCT02899052) Previously generated WGS to an average coverage ~22 × was used Paired samples of peripheral blood mononuclear cell (PBMC) DNA and plasma circulating cell-free DNA (cfDNA) were analyzed by dPCR at timepoints after Ven-based treatment Of the 90 t(11;14)+ pts by FISH, 160 t(11;14) breakpoints were identified by WGS in 74 pts (concordance in Table) At the time of data cutoff, dPCR assays were designed and evaluated in 8 t(11;14)+ pts; 7/8 (88%) and 6/8 (75%) pts had detectable t(11;14) in cfDNA or PBMCs, respectively Higher levels of t(11;14) mutant allele frequency (MAF) were observed in cfDNA compared with PBMCs After Ven-based treatment, t(11;14) MAF in cfDNA became undetectable in pts with a complete response In conclusion, this approach has the capability to reconstruct t(11;14) breakpoints from WGS data that is highly concordant with FISH; translocations appear more readily detectable in cfDNA than PBMC samples from pts with MM SAGAsign assays detected and monitored t(11;14) in liquid biopsies thus highlighting its potential utility for identifying pts with t(11;14) for targeted therapies Concordance between WGS and FISH testing for t(11;14) Samples, n FISH+ FISH− Total WGS+ 74 11 83 WGS− 16 169 187 Total 90 180 270 Concordance, % n/N 95% CI t(11;14) positive 82.2 74/90 72.7-89.5 t(11;14) negative 93.9 169/180 89.3-96.9 Overall testing 90.0 243/270 85.8-93.3 Citation Format: Xiaotong Li, Lao H. Saal, Christian Brueffer, Yilun Chen, Johanna Asklin, Saman Alvi, Srinivas Venkatram, Jeremy A. Ross. Detection and monitoring of t(11;14) in liquid biopsies from patients with relapsed/refractory multiple myeloma treated with venetoclax-based regimens. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5710.
Abstract 3785: Telomerase RNA component lncRNA regulates hsa-miR-320 family and promotes prostate cancer metastasis
Authors: Mandisa Mbeje, Jeyalakshmi Kandhavelu, Clement Penny, Zodwa Dlamini, Rahaba Marima
Journal: Cancer Research (2023)

Abstract Telomerase RNA component (TERC) is a long non-coding (lncRNA) associated with prostate cancer progression and has novel prognostic biomarker potential. Differential methylation patterns of lncRNAs affect their expression levels, leading to cancer. This study aimed to profile and elucidate differential lncRNA expression patterns in prostate cancer (PCa). A 384-well plate of PCa associated lncRNA gene array panel was used in castration resistant PC-3 PCa cells vs androgen-sensitive PCa LNCaP cells. Annotation and enrichment analysis of lncRNA differential gene expression was performed using a human lncRNA sets database, LncSEA. Furthermore, digital droplet PCR (ddPCR) was used to verify the PCR array results. Up or down-regulation of ±2 and p &amp;lt;0.05 were considered significant. Decreased hsa-miR-320 gene family expression has been reported in various tumors including PCa. However, the precise mechanisms of hsa-miR-320 gene family in PCa remain to be elucidated. Thirty six of 84 lncRNAs were shown to be upregulated, while 14% of the lncRNA genes were downregulated. Notably, TERC lncRNA was upregulated in high metastatic PC-3 cells. Hypermethylation patterns of this lncRNA in high metastatic PC-3 cells was also shown by enrichment analysis. Furthermore, TERC lncRNA was demonstrated to regulate the hsa-miR-320 family, suggesting a correlation between TERC hypermethylation and downregulation of hsa-miR-320 gene family expression in PCa, as revealed by bioinformatics analysis. TERC lncRNA promotes PCa cell proliferation, migration, invasion and metastasis by sponging hsa-miR-320 family. This TERC/hsa-miR-320 interaction holds potential to understanding PCa prognostic mechanisms by lncRNAs and may also be targeted for novel therapeutics. Citation Format: Mandisa Mbeje, Jeyalakshmi Kandhavelu, Clement Penny, Zodwa Dlamini, Rahaba Marima. Telomerase RNA component lncRNA regulates hsa-miR-320 family and promotes prostate cancer metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3785.
Abstract 4116: Modulating gut microbiota to improve intrahepatic immunity against hepatocellular cancer
Authors: Xiaogiang Qi, Ming Yang, Lixin Ma, Jonathan Mitchem, Jussuf Kaifi, Shiyou Chen, Aaron Ericsson, Eric Kimchi, Kevin Staveley-O’Carroll, Guangfu Li
Journal: Cancer Research (2023)

Abstract Gut microbiota plays a pivotal role in the pathogenesis of hepatocellular cancer (HCC), significantly affecting the HCC treatment. It has been reported that the HCC patients’ response to the immunotherapy of PD-1/PD-L1 blockade was associated with their gut microbiota profiles. However, the impact of gut microbiota on anti-HCC immunity and its underlying mechanism are poorly understood. Treating HCC-bearing mice with a specific and non-hepatotoxic antibiotic cocktail caused the increased relative abundance of specific commensal bacteria such as Bacteroides, resulting in suppression of HCC growth and development which was involved in the activation of intrahepatic antitumor immune responses. Gut microbiota recolonization of Bacteroides thetaiotaomicron (B. th) in gut-sterilized HCC-bearing mice significantly improved the therapeutic efficacy of anti-PD-1 antibody (αPD-1 Ab) against HCC. Fecal microbiota transplantation (FMT) from HCC patients who received and responded to αPD-1 Ab treatment improved the efficacy of αPD-1 Ab treatment against HCC in mice model. Mechanistic studies demonstrated that the modulation of Krüppel-like factor 2 (KLF2)/Toll-like receptor 9 (TLR9) signaling and the accumulation of CpG-enriched genomic DNAs of B. th in livers/tumors activated the tumor antigen-specific CD8+ T cells through the dendritic cell in a TLR9-dependent manner. In conclusion, gut microbiota as a causative factor can be targeted to improve anti-HCC immunotherapy. Citation Format: Xiaogiang Qi, Ming Yang, Lixin Ma, Jonathan Mitchem, Jussuf Kaifi, Shiyou Chen, Aaron Ericsson, Eric Kimchi, Kevin Staveley-O’Carroll, Guangfu Li. Modulating gut microbiota to improve intrahepatic immunity against hepatocellular cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4116.
Abstract 6083: Extensive epigenetic and transcriptomic donor-specific differences observed in iPSC derived allogenic NK (iNK) cells
Authors: Rohith Srivas, Snehal Nariya, Melissa Rojsza, Barry A. Morse, Ohad Manor, Rupesh Amin, Luis Borges
Journal: Cancer Research (2023)

Abstract Several autologous CAR-T cell therapies have been approved for the treatment of B cell lymphomas and leukemias and a number of trials are in progress to investigate the use of allogeneic, donor derived CAR-T and CAR-NK cell therapies for multiple tumor indications. However, sourcing cell donors, editing cells and generating large batches of clinical grade allogeneic CAR-T and CAR-NK can be challenging. To overcome these difficulties, we are developing NK and T cell-based therapies derived from induced pluripotent stem cells (iPSCs). iPSCs have the capacity to be genetically engineered, enabling precise edits that can enhance the function of cell therapies, and indefinitely expanded in culture, allowing for the production of highly uniform master cell banks. Yet, an open question of this system is the extent to which the donors’ genetic background shapes the phenotype of the iPSC-derived NK and T cells. To answer this question, we measured the genome-wide landscape of chromatin accessibility and gene expression in iNK cells generated from multiple donors. Donor background was linked to significant changes in chromatin accessibility (~30% of regions tested) and expression (~15% genes). We found accessibility changes at binding sites for transcription factors regulating various aspects of NK cell function, including differentiation (GATA2, EOMES, and ETS1), activation (AP-1, T-bet), and cytokine production (STAT3, STAT5), indicating that the donor background could impact the functionality of iPSC-derived NK cells. In particular, we noted that iNK cells derived from one donor, which had decreased effector functions compared to other cell lines, showed increased accessibility at BACH2 binding sites, a key negative regulator of NK cell function. iNK cells derived from this donor also showed an increase in expression of genes linked to NK cell differentiation and cell development, and a decrease in genes involved in cell cycle, cell proliferation, and inflammatory response pathways. Taken together, these data indicate the importance of assessing the impact of donor background on iPSC derived cell therapies through a variety of functional and genomic assays. Citation Format: Rohith Srivas, Snehal Nariya, Melissa Rojsza, Barry A. Morse, Ohad Manor, Rupesh Amin, Luis Borges. Extensive epigenetic and transcriptomic donor-specific differences observed in iPSC derived allogenic NK (iNK) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6083.
Abstract 5333: Combining chemoproteomics with machine learning identifies functionally active covalent fragments for hard-to-drug cancer drivers
Authors: Johannes C. Hermann, Robert Everley, Laura Marholz, Matthew Berberich, Tzu-Yi Yang, Yu-Hsin Chao, Abduselam K. Awol, Michael Shaghafi, Han Yoon, Rohan Varma, Reed Stein, Karsten Krug, Emily Lachtara, Daniel Erlanson, Chris Varma, Kevin R. Webster
Journal: Cancer Research (2023)

Abstract a) Many cancer drivers are considered “undruggable” and without targeted treatments because they lack binding sites for conventional small molecules. Here, we introduce The FRONTIER™ Platform applying machine learning (ML), chemoproteomics and covalent chemistry to identify binding sites and cell-active covalent fragments across the human proteome, including against most cancer drivers and previously “undruggable” targets. Molecules tested in functional assays are active and can serve as starting points for new drug discovery initiatives. b) We are using mass spectrometry and data analysis workflows to perform high-throughput chemoproteomic profiling experiments. These experiments identify hits across the proteome using different cancer-relevant cell backgrounds and characterize binding sites for drug discovery. Customized ML algorithms using chemoproteomic, genomic and structural data to characterize and prioritize identified binding sites for covalent drug discovery. The performance of the platform allows the profiling of thousands of compounds from a custom-built library that has been optimized by ML for covalent fragment-based drug discovery. The nature of the fragment hits and the ability to map them to and focus on preferred binding sites for covalent drugs enables accelerated lead generation. c) We show details of the platform highlighting library design concepts and the hotspot map with binding site prioritization algorithms. We show coverage and applicability across important cancer target classes and signaling pathways. Covalent fragment hits have been identified for multiple difficult cancer targets, including KRAS, p53, STAT3, KEAP1, PTPN11 and others. The platform also identifies ligands for novel allosteric binding sites in established oncology targets such as CDK4, PI3KCA and BTK. We will highlight how discovered ligands show functional activity in orthogonal assays, demonstrating their fitness for drug discovery campaigns and target validation experiments. d) Undruggable targets across a variety of cancer target classes have become druggable. Citation Format: Johannes C. Hermann, Robert Everley, Laura Marholz, Matthew Berberich, Tzu-Yi Yang, Yu-Hsin Chao, Abduselam K. Awol, Michael Shaghafi, Han Yoon, Rohan Varma, Reed Stein, Karsten Krug, Emily Lachtara, Daniel Erlanson, Chris Varma, Kevin R. Webster. Combining chemoproteomics with machine learning identifies functionally active covalent fragments for hard-to-drug cancer drivers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5333.
Abstract 2243: Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
Authors: Pie-Che Chen, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen, Michael W.Y. Chan
Journal: Cancer Research (2023)

Abstract Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. In this study, we performed RNA-Seq to examine genes that are differentially expressed after treatment with CPH in UC cells. Our result showed that several genes, including IRF6, were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, which is due to promoter hypomethylation and enrichment of H3K27 acetylation, as well as H3K4 mono-methylation. Importantly, treatment of CPH can inhibit tumor growth in a syngeneic mouse tumor model. The tumor growth can be further inhibited by combination treatment of CPH and immune checkpoint blockade. Flow cytometric analysis of the tumor found that NK cells are significantly enriched in the CPH treatment group, as compared to DMSO control. Co-culture experiments confirmed that UC cells pretreated with CPH showed an increased NK-92-mediated cytotoxicity. In conclusion, these results suggested that treatment of CPH can inhibit tumor growth, by epigenetic priming of IRF6 in UC. The role of CPH in eliciting anti-tumor innate immune response deserves further investigation. Citation Format: Pie-Che Chen, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen, Michael W.Y. Chan. Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2243.
Abstract 3774: MiR-34b promotes cellular senescence and ROS generation in human cervical cancer cells
Authors: K J Sindhu, Devarajan Karunagaran
Journal: Cancer Research (2023)

Abstract Background: Cervical cancer is one of the most common cancers in women worldwide, particularly in low- and middle-income countries. Due to low surveillance and late detection, it is one of the major health issues leading to high mortality rates. MicroRNA-34 family (miR-34a, b, c) is thought to be tumor suppressive in several cancers but the mechanistic basis is not clear. Methods: Stable cell lines were generated with inducible hsa-miR-34b lentiviral vector from Dharmacon and maximal time and dose for induction of miR-34b with doxycycline were determined. Cell viability studies on HeLa, SiHa and C33A were investigated by MTT assay. Acridine orange/Ethidium bromide (AO/EB), senescence associated β-galactosidase (SA- β gal) assays for apoptosis and senescence and assessment of DNA damage (γH2AX) were performed. Total reactive oxygen species (ROS), superoxide, hydroxyl and peroxynitrite and H2O2 radicals were quantitated by DCFDA, DHE, HPF dyes and pHyper-dMito plasmid, respectively. Results: Overexpression of miR-34b reduced cell viability in cervical cancer cell lines except SiHa. Further investigation by AO/EB staining revealed no significant increase in the proportion of apoptotic cells on overexpression of miR-34b. Analysis of SA- β gal on overexpression of miR-34b revealed an increase in the proportion of senescent population in all 3 cell lines. Increased DNA damage is also observed in agreement with an increase in cellular senescence. In addition, an increase in oxidative stress was observed in miR-34b overexpressing cell lines as total ROS was elevated in all 3 cell lines with increased superoxide, hydroxyl and peroxynitrite and H2O2 radicals in HeLa and C33A while SiHa showed increased levels of H2O2 radicals with no significant change in other radicals. Conclusions: Overexpression of miR-34b can promote an increase in cellular senescence and oxidative stress in cervical cancer. The differential action in different cell lines may be due to the difference in expression of miR-34b in these cell lines. Our results highlight the potential of miR-34b to be used for therapeutic intervention in cervical cancer. Citation Format: K J Sindhu, Devarajan Karunagaran. MiR-34b promotes cellular senescence and ROS generation in human cervical cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3774.